Attentional Dysfunction in Fragile X Syndrome

超出所提供的空间。该项目的目的是了解脆性X综合征（FXS）中注意力缺陷的神经系统，以便设计有效的治疗方法。FXS的注意缺陷特征比他们的“i”更严重。问：我们假设三种不同的大脑系统的缺陷相互作用导致了这些极端的注意力困难。首先，执行功能受损已被证明会导致FXS的注意力缺陷。其次，感官信息的异常处理可能会损害注意力，并导致过度觉醒，从而损害注意力。最后，下丘脑-垂体-肾上腺轴的异常可能导致觉醒和认知功能下降。我们将使用新开发和验证的五臂迷宫注意力测量。我们还将探讨分散注意力的刺激对任务表现的影响。主动回避是一项任务，我们已经发现了注意力和情感因素的深刻影响。由于该任务的参数可以系统地变化以确定学习问题的性质，因此该任务将用于确定感官和情感困难对认知表现的影响。HPA轴尚未在Fmr1 KO小鼠中进行研究，但与对照组相比，FXS患者在应激后恢复到基础皮质酮水平的速度更慢，Eberwine和Greenough的发现可以预测这一结果，即FMRP与糖皮质激素受体（GR）结合，导致Fmr1 KO小鼠海马中的GR水平下降25%。我们将对皮质酮的日常节律、对应激的反应和从应激中恢复进行彻底的检查。在其他动物模型中，GR对HPA轴的降低影响很难预测，因此将检查整个轴的标记物（GR， MR， CRF， ACTH， POMC皮质酮）的大脑和肾上腺表达，因为这些分子在大脑中的表达可以对认知和行为产生深远的影响。当我们对注意力和认知表现有了良好的测量，并且知道HPA轴的异常情况时，我们可以选择可能影响我们假设参与FXS注意缺陷的三个系统的药物。这些药物的单独或联合试验将确定每个系统的相对作用，并导致对FXS这一重要问题的联合治疗。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. The objective of this project is to understand the neural systems involved in the attention deficits in fragile X syndrome (FXS), so that effective treatments can be devised. The attention impairment characteristic of FXS are more severe than would be expected for their'I.Q, We hypothesize that defects in three different brain systems interact to produce these extreme attention difficulties. First, impairment of executive function ha been shown to contribute to attention deficits in FXS. Second, abnormal processing of sensory information likely impairs attention as well as leading to over arousal that impairs attention. Finally, abnormalities in the hypothalamic pituitary adrenal axis likely contribute to arousal and lower cognitive function. We will use the newly developed and validated 5-arm maze attention measure. Effects of distracting stimuli on performance on this task will also be explored. Active avoidance is a task on whichWe have found profound effects of attentional and emotional factors. As parameters of this task can be varied systematically to determine the nature of the learning problem, this task will be used to determine the impact of the sensory and emotional difficulties on cognitive performance. The HPA axis has not been studied in the Fmr1 KO mouse, but humans with FXS return to basal corticosterone levels more slowly after stress than do controls, a result that would be predicted by the finding from Eberwine and Greenough that FMRP binds to the glucocorticoid receptor (GR), resulting in a 25% decrease in GR levels Inthe hippocampus in the Fmr1 KO mouse. We will conduct a thorough examination of the corticosterone daily rhythm, response to and recovery from stress, In other animal models of reduced GR effects on the HPA axis have been difficult to predict, so brain and adrenal expression of markers for the entire axis (GR, MR, CRF, ACTH, POMC corticosterone) will be examined, as expression of these molecules in the brain can have profound effects upon cognition and behavior. All of these aims build to the final aim, When we have good measures of attention and cognitive performance and know the abnormalities in the HPA axis, we can select drugs likely to impact the three systems we hypothesize to be involved in the attention deficits in FXS. Individual md combination tests of these drugs will determine the relative roles of each of these systems, and lead to ¿-,-combination treatments for this Important problem In FXS. PERFORMANCE SITE ========================================Section End===========================================